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Aim: To review safety and efficacy outcomes in studies of first-line maintenance therapies for advanced ovarian cancer. Methods: A systematic literature review was performed (27 February 2020) to identify clinical outcomes including progression-free survival (PFS), overall survival (OS) and Grade ≥3 adverse events. Results: Overall 50 references met prespecified criteria; 18 studies evaluated 10 different agents, including PARP inhibitors. PFS was an end point in 16 trials and OS in 12 trials. PARP inhibitors reported better PFS hazard ratios (HRs: 0.59–0.68) compared with other classes; no mature OS data were identified. Safety reporting was inconsistent. Conclusion: Reported PFS HRs were better for PARP inhibitors than for other ovarian cancer maintenance therapies; overall survival data remain immature.

BACKGROUND: Ovarian cancer (OC) is the fifth leading cause of cancer death in women and has the highest mortality rate of gynecological cancers. Niraparib was recently approved by the FDA for the maintenance treatment of adult patients with advanced epithelial OC in complete or partial response to first-line platinum-based chemotherapy (PBC) regardless of biomarker status. OBJECTIVE: To estimate the direct economic impact on US payers of adding niraparib as a first-line maintenance therapy for patients with advanced OC. METHODS: The model considered 2 scenarios: a current scenario in which niraparib does not have regulatory approval for first-line maintenance therapy and a future scenario in which niraparib has regulatory approval for first-line maintenance therapy. The budget impact was calculated as the difference in cost between the 2 scenarios. The budget impact model (BIM) considered 2 different US health care payer perspectives: a commercial health plan and a Medicare plan. Both payer perspectives were assumed to have a hypothetical 1 million affiliates that were covered. Epidemiological data was used to estimate the eligible incident population of patients with OC. Active surveillance, bevacizumab (as a monotherapy), and olaparib (as a monotherapy restricted to patients with the breast cancer gene [BRCA] mutation) were included in the model as alternative maintenance treatment options (maintenance treatment options required 1% market share for inclusion). Cost categories considered in the BIM included diagnostic testing, treatment acquisition and administration, treatment-emergent adverse events, and subsequent therapy. Results were presented as an incremental budget impact to payers over 3 years. RESULTS: For a commercial health plan of 1 million affiliates, the estimated impact of adding niraparib as a first-line maintenance treatment option for advanced epithelial OC was calculated as $87,906, $93,106, and $87,037 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.007. For a Medicare health plan of 1 million affiliates, the estimated impact was calculated as $206,785, $219,017, and $204,739 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.018. One-way sensitivity analyses suggested that budget impact was most sensitive to the treatment duration and market share of niraparib, the non-treatment-specific data on overall survival rates, and the treatment duration of bevacizumab. Treatment of drug-specific adverse events had little impact on the budget model. CONCLUSIONS: The model estimated a minimal budget impact to both a commercial or Medicare health plan following the introduction of niraparib as a first-line maintenance therapy for patients with advanced epithelial OC who are in complete or partial response to first-line PBC regardless of biomarker status. DISCLOSURES: This study was financially supported by GlaxoSmithKline. Liu, Hawkes, Maiese, and Hurteau are employees of GlaxoSmithKline. Travers was employed by GlaxoSmithKline at the time of this study. Spalding and Walder are employees of FIECON Ltd., which was contracted by GlaxoSmithKline to develop the budget impact model used in this study.

Selecting a first-line (1L) maintenance option for ovarian cancer is challenging given the variety of therapies, differing trials, and the lack of head-to-head data for angiogenesis and poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, indirect treatment comparisons (ITCs) can aid treatment decision making. This study assessed the feasibility of two ITCs, a network meta-analysis (NMA) and a population-adjusted ITC (PAIC), comparing the efficacy of the PARP inhibitor niraparib in the PRIMA trial (NCT02655016) with other 1L maintenance treatments. A systematic literature review was conducted to identify trials using the Cochrane Handbook for Systematic Reviews of Interventions to assess differences in trial design, population characteristics, treatment arms, and outcome measures. All 12 trials identified were excluded from the NMA due to the absence of a common comparator and differences in survival measures and/or inclusion criteria. The PAIC comparing PRIMA and PAOLA-1 trials was also not feasible due to differences in inclusion criteria, survival measures, and the previous receipt of chemotherapy/bevacizumab. Neither ITC met recommended guidelines for analysis; the results of such comparisons would not be considered appropriate evidence when selecting 1L maintenance options in ovarian cancer. ITCs in this setting should be performed cautiously, as many factors can preclude objective trial comparisons.

Background Patients with rheumatoid arthritis (RA) commonly experience pain despite the availability of disease-modifying treatments. Sleep disturbances are frequently reported in RA, with pain often a contributing factor. The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference and Sleep Disturbance item banks were initially developed to provide insights into the patient experience of pain and sleep, respectively, though they were not specifically intended for use in RA populations. This study evaluated the content validity of the PROMIS Pain Interference and Sleep Disturbance item banks in RA and identified relevant content for short forms for patients with RA that achieved high measurement precision across a broad range of health. Methods A qualitative approach consisting of hybrid concept elicitation and cognitive debriefing interviews was used to evaluate the content validity of the item banks in RA. Interviews were semi-structured and open-ended, allowing a range of concepts and responses to be captured. Findings from the qualitative interviews were used to select the most relevant items for the short forms, and psychometric evaluation, using existing item-response theory (IRT) item parameters, was used to evaluate the marginal reliability and measurement precision of the short forms across the range of the latent variables (i.e. pain interference and sleep disturbance). Results Thirty-two participants were interviewed. Participants reported that RA-related pain and sleep disturbances have substantial impacts on their daily lives, particularly with physical functioning. The PROMIS Pain Interference and Sleep Disturbance item banks were easy to understand and mostly relevant to their RA experiences, and the 7-day recall period was deemed appropriate. Qualitative and IRT-based approaches identified short forms for Pain Interference (11 items) and Sleep Disturbance (7 items) that had high relevance and measurement precision, with good coverage of the concepts identified by participants during concept elicitation. Conclusion Pain and sleep disturbances affect many aspects of daily life in patients with RA and should be considered when novel treatments are developed. This study supports the use of the PROMIS Pain Interference and Sleep Disturbance item banks in RA, and the short forms developed herein have the potential to be used in clinical studies of RA.

Introduction/Background Maintenance therapies have changed the treatment landscape in ovarian cancer (OC) in recent years. Here we sought to review safety and efficacy outcomes in clinical trials of first-line maintenance therapies. Methodology A systematic literature review (SLR) was performed on 27 February 2020 to identify clinical outcomes associated with first-line maintenance therapies and maintenance therapies initiated alongside first-line chemotherapy followed by a maintenance phase for advanced OC. Randomised controlled trials (RCTs), non-RCTs and observational studies were eligible. Selection criteria following the PICOS (population, interventions, comparators, outcomes and study type) principle were specified. Outcomes of interest were progression-free survival (PFS), overall survival (OS), and treatment emergent adverse events (TEAEs). Selected studies were then extracted by one reviewer and assessed for quality by a second reviewer. Disagreements were resolved by a third reviewer when required. Results This SLR retrieved 8,631 unique references of which a total of 50 references were accepted and extracted in this SLR (figure 1). The 50 references identified covered 18 clinical trials that evaluated maintenance therapies in OC patients following one prior line of chemotherapy. Of these 18 trials, 12 were RCTs and the remaining 6 were observational, dose escalation and retrospective review studies. Of the 18 trials, only 2 did not assess PFS as an efficacy endpoint (NCT00058435 and MIMOSA). PARP inhibitors across the board reported a better PFS hazard ratio (HR) than other OC maintenance therapies (table 1). No pattern was identified in relation to PFS amongst patients who were treated with a maintenance therapy following first-line platinum-based chemotherapy versus those who received a maintenance drug concurrently with first-line platinum-based chemotherapy and then continued with the maintenance treatment. OS was reported as a secondary endpoint in 12 trials (MIMOSA, AGO-OVAR16, SOLO-1, ICON-7, GOG-0218, AGO-OVAR12, VELIA/GOG-3005, TRINOVA-3, ESME, CHIVA/GINESCO, PRIMA and PAOLA-1). Only PARP inhibitor-containing therapies reported significant OS HRs below 1 across all trial populations. TEAEs were reported for 11 of the 18 trials. Discontinuation due to AEs was reported in 10 of the 18 trials. Conclusion Therapies that included PARP inhibitors reported better PFS HR than other OC maintenance therapies. In study populations including both BRCA mutation positive and wild type, clinical benefit is conferred by both olaparib plus bevacizumab and niraparib as indicated by PFS. OS data remain immature. Disclosures This study was funded by GlaxoSmithKline. Clinical Trial Registration: N/A Dr Guy and Walder report institutional reimbursements from GlaxoSmithKline. Drs. Travers, Hawkes, Malinowska, and Gupta are employees of GlaxoSmithKline.

Introduction/Background Although randomised controlled trials (RCTs) have demonstrated the benefit of PARP inhibitors and bevacizumab as monotherapies and combination therapies, there is limited direct head-to-head evidence of their relative clinical efficacy. In the PRIMA study, niraparib demonstrated a clinically significant improvement in progression-free survival (PFS) compared with placebo, as a first-line (1L) ovarian cancer (OC) maintenance therapy. The objectives of the study were to assess feasibility of an indirect treatment comparison (ITC) and a population-adjusted indirect treatment comparison (PAIC) for estimating the relative efficacy of niraparib compared with olaparib, olaparib plus bevacizumab, and bevacizumab as maintenance following 1L chemotherapy in OC. The study focused on fully powered statistical cohorts. Methodology Trials included in the ITC analysis were based on a systematic literature review conducted in February 2020. Guidelines from the Cochrane Handbook for Systematic Reviews of Interventions were used to assess the level of heterogeneity across the studies in terms of designs, population characteristics, treatment arms and outcome measures. The feasibility of PAIC for the PRIMA and PAOLA-1 trials was assessed based on assumptions outlined in the guidance by the Decision Support Unit in NICE DSU Technical Support Document 18; PFS was the outcome for the analysis. Results All 12 RCTs assessed for ITC feasibility were excluded based on various factors including: the lack of a common comparator with PRIMA within the network (ICON-7, GOG-0218, PAOLA-1, VELIA/GOG-3005); differing measurement of PFS and overall survival starting timepoint due to trial design (ICON-7, GOG-0218, VELIA/GOG-3005); inclusion of stage III patients with no visible residual disease following debulking surgery (PAOLA-1, SOLO-1, VELIA/GOG-3005); disparity between disease biomarker (SOLO-1). For the PAIC, three fundamental differences between the PRIMA and PAOLA trials were identified; inclusion criterion related to residual disease was wider in PAOLA meaning that the ‘conditional constancy of absolute effects’ was violated; receipt of neoadjuvant chemotherapy was identified as a confounding factor that would bias a PAIC; discrepancies in the assessment of type and frequency of measurement of the PFS outcome. Conclusions Based on the evidence currently available, neither an ITC nor PAIC would meet current guidelines, such as those outlined by the International Society for Pharmacoeconomics and Outcomes Research, for these analyses. Their results would not be considered appropriate evidence for use in clinical decision making or reimbursement decisions. The extent of imbalance caused by differences in the patient inclusion/exclusion criteria for intended comparisons is unknown and a recognised limitation of PAICs. Disclosures This study was funded by GlaxoSmithKline. Due to lengthy author disclosures, author COI information will be provided directly to the congress.

Background The human monoclonal antibody otilimab inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in immune-mediated inflammatory conditions. We aimed to evaluate the efficacy, safety, and key patient-reported outcomes related to pain in patients with active rheumatoid arthritis receiving otilimab. Methods This phase 2b, dose-ranging, multicentre, placebo-controlled study was done at 64 sites across 14 countries. Patients aged 18 years or older with rheumatoid arthritis who were receiving stable methotrexate were randomly assigned (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5 mg, 45 mg, 90 mg, 135 mg, or 180 mg, plus methotrexate, once weekly for 5 weeks, then every other week until week 50. The randomisation schedule was generated by the sponsor, and patients were assigned to treatment by interactive response technology. Randomisation was blocked (block size of six) but was not stratified. Investigators, patients, and the sponsor were blinded to treatment. An unblinded administrator prepared and administered the study drug. The primary endpoint was the proportion of patients who achieved disease activity score for 28 joints with C-reactive protein (DAS28-CRP) 3·2 (week 24) escaped to otilimab 180 mg. Patients who escaped were treated as non-responders in their original assigned group. Safety endpoints were incidence of adverse events and serious adverse events, infections, and pulmonary events. Efficacy and safety outcomes were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02504671. Findings Between July 23, 2015, and Dec 29, 2017, 222 patients were randomly assigned (37 to each group). 86 (49%) of 175 escaped to otilimab 180 mg at week 12 and 57 (69%) of 83 at week 24. At week 24, the proportion of patients with DAS28-CRP Interpretation Otilimab plus methotrexate was well tolerated and, despite not achieving the primary endpoint of DAS28-CRP remission, there were improvements compared with placebo in disease activity scores. Of note, patients reported significant improvement in pain and physical function, supporting further clinical development of otilimab in rheumatoid arthritis.

Objectives: Poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated efficacy in ovarian cancer (OC). Since December 2014, several PARPi have been approved as third- or fourth-line treatment agents, as well as maintenance treatment, in patients with platinum-sensitive recurrent OC (PSROC), and maintenance treatment in front-line OC. Factors affecting PARPi use in the maintenance setting and potential population-specific disparities in PARPi use are unknown. The aim of this study was to explore if age or other factors influence the use of PARPi maintenance treatment in PSROC. Methods: This retrospective real-world study used the Flatiron Health database, a longitudinal, demographically and geographically diverse electronic health record-derived, de-identified database from ~280 cancer clinics nationwide (~800 sites of care) representing US cancer patients. Patients diagnosed with invasive ovarian, fallopian tube, and/or primary peritoneal cancer, collectively referred to as OC, from January 1, 2011, to July 31, 2020, who received ≥2 lines of platinum-based treatment, were platinum sensitive, and did not receive prior PARPi, were included. PARPi use as PSROC maintenance was compared using a chi-square test or t-test across several factors, including BRCA mutational (BRCAm) status, age, race, practice setting, and geographical location. Results: We identified 545 patients who met the inclusion criteria. Of those, 203 (37%) received PARPi maintenance. Of the 84 patients with BRCAm, 53 (63%) received a PARPi (Table). In contrast, of the 361 BRCA wild-type (BRCAwt) patients, 119 (33%) received PARPi. Patients with a BRCAm were more likely to be treated with a PARPi vs patients who were BRCAwt (P Download : Download high-res image (160KB) Download : Download full-size image Conclusions: In this real-world study, BRCAm status and younger age were associated with the use of PARPi as maintenance treatment in PSROC. No other factor included in this analysis was found to be associated with disparities in the use of PARPi maintenance. However, PARPi uptake still needs improvement across all groups.Funding: GlaxoSmithKline, Waltham, MA, United States

Background GSK3196165 is a human mAb that inhibits GM-CSF, a key driver in a broad range of immune-mediated conditions (Hamilton, 2016). In trials of patients with RA, inhibition of GM-CSF signaling has resulted in clinical benefit. GM-CSF is not only a key mediator of inflammation, but emerging science suggests it is also an important regulator of pain. Objectives To evaluate the treatment effect of GSK3196165 on pain, fatigue, physical functioning, mental functioning and global assessment of disease, in patients with moderate-to-severely active RA. Methods 222 adult patients with active, moderate-severe RA (ACR 2010 criteria), ≥4 each of swollen and tender joints, DAS28(CRP) ≥3.2 and CRP ≥5.0 mg/L, were randomized equally to placebo or GSK3196165 22.5mg, 45mg, 90mg, 135mg or 180mg SC weekly for 5 injections, then every other week until Week 50. The Patient Reported Outcomes (PROs) measured throughout the study included, pain Visual Analogue Scale (VAS), Patient’s Global Assessment of Arthritis (PtGA), Health Assessment Questionnaire - Disability Index (HAQ-DI), Brief Fatigue Inventory (BFI) Question 3, the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F), and the 36-item short form health survey (SF-36). The primary outcome was the proportion of patients who achieved remission (DAS28(CRP) Results 37 patients were randomised to each treatment group. The observed GSK3196165 pharmacokinetic exposures were lower than anticipated but despite this, there was a rapid and substantial improvement in RA symptoms in patients treated with GSK3196165 compared with placebo. The table below summarizes the change from baseline data for the GSK3196165 180 mg dose and placebo at Week 12. An increase in the FACIT-F and SF-36 scores and a decrease in all other scores indicate an improvement in RA symptoms. Conclusion The results of this Phase IIb study showed that GSK3196165 substantially improved the scores of a range of PRO measures among RA patients. In particular, there was a highly significant improvement in pain; a key symptom of RA. These effects were observed despite achieving much lower drug exposure than predicted. Further studies are required to confirm the additional patient relevant benefits that are expected to arise from increased exposure to GSK3196165. References [1] Hamilton JA, Cook AD, Tak PP. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nat Rev Drug Discov 2016; 16:53-70 [2] Buckley C, et al. A Phase IIb Dose-Ranging Study of Anti-GM-CSF with Methotrexate Treatment in Patients with Rheumatoid Arthritis (RA) and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2018;70 (Suppl 10): abs 1938 Disclosure of Interests Chris Buckley Consultant for: GlaxoSmithKline, Jesus Simon Campos: None declared, Vyacheslav Zhdan: None declared, Brandon Becker Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, Deven Chauhan Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, Katherine Davy Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, Carol Hawkes Shareholder of: I own shares in GlaxoSmithKline, Employee of: I am currently an employee of GlaxoSmithKline, David Inman Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, Mark Layton Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, Jatin Patel Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, Didier Saurigny Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, Nina Mitchell Shareholder of: GlaxoSmithKline, Employee of: Former GlaxoSmithKline employee, Russell Williamson Shareholder of: GlaxoSmithKline, Employee of: Former GlaxoSmithKline employee, Paul Peter Tak Shareholder of: GlaxoSmithKline, Employee of: Former GlaxoSmithKline employee

In the EGF30008 and TAnDEM (TrAstuzumab in Dual HER2 ER-positive Metastatic breast cancer) trials, anti-HER2 therapy plus an aromatase inhibitor (lapatinib + letrozole (LAP + LET) and trastuzumb + anastrozole (TZ + ANA), respectively) improved time to progression versus aromatase inhibitor monotherapy (LET and ANA, respectively) in post-menopausal women with previously untreated hormone receptor-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer.A partitionedsurvival analysis model using data from EGF30008 and published results of TAnDEM and other literature was used to evaluate the incremental direct medical cost per quality-adjusted life year (QALY) gained with LAP + LET versus LET, ANA, and TZ + ANA in post-menopausal women with previously untreated HR+ and HER2+ metastatic breast cancer from the UK National Health Service (NHS) perspective.Incremental costs for LAP + LET are £ 34,737 versus LET, £ 35,995 versus ANA, and £ 5,513 versus TZ + ANA. Corresponding QALYs gained are 0.467, 0.601, and 0.252 years. Cost/QALY gained with LAP + LET is £ 74,448 versus LET, £ 59,895 versus ANA, and £ 21,836 versus TZ + ANA. Given a threshold of £ 30,000/QALY, the estimated probability that LAP + LET is cost-effective is 1.4% versus LET, 9.2% versus ANA, and 51% versus TZ + ANA.Based on criteria for the evaluation of health technologies in the UK (£ 30,000/QALY), LAP + LET is not likely to be cost-effective versus aromatase inhibitor monotherapy but may be cost-effective versus TZ + ANA, although the latter comparison is associated with substantial uncertainty.In den Studien EGF30008 und TAnDEM (Trastuzumab in Dual HER2 ER-Positive Metastatic Breast Cancer) zeigte sich bei Anti-HER2-Therapie plus Aromataseinhibitor (Lapatinib + Letrozol (LAP + LET) bzw. Trastuzumab + Anastrozol (TZ + ANA)) gegenüber einer Aromataseinhibitor-Monotherapie (LET bzw. ANA) eine verbesserte Zeitspanne bis zur Progression bei postmenopausalen Frauen mit zuvor unbehandeltem Hormonrezeptor-positivem (HR+) und HER2-positivem (HER2+) metastatischem Brustkrebs.Ein Modell zur abschnittsweisen Überlebensanalyse auf der Basis von Daten aus EGF30008 sowie publizierten Ergebnissen aus TAnDEM und anderer Literatur wurde angewendet, um die zunehmenden direkten medizinischen Kosten pro qualitätskorrigiertem Lebensjahr (QALY), das durch LAP + LET versus LET, ANA bzw. TZ + ANA bei postmenopausalen Frauen mit zuvor unbehandeltem HR+ und HER2+ metastatischem Brustkrebs gewonnen wurde, aus der Perspektive des britischen nationalen Gesundheitsversorgungssystems (NHS) zu evaluieren.Die Kostenzuwächse für LAP + LET betragen 34 737 £ versus LET, 35 995 £ versus ANA und 5513 £ versus TZ + ANA. Die entsprechenden gewonnenen QALYs belaufen sich auf 0,467, 0,601 and 0,252 Jahre. Die Kosten pro gewonnenem QALY durch LAP + LET sind 74 448 £ versus LET, 59 895 £ versus ANA und 21 836 £ versus TZ + ANA. Bei einem Schwellenwert von 30 000 £/QALY beträgt die geschätzte Wahrscheinlichkeit, dass LAP + LET kosteneffektiv ist, 1.4% versus LET, 9.2% versus ANA and 51% versus TZ + ANA.Auf der Basis von Kriterien zur Evaluation von Gesundheitstechniken in Großbritannien (30 000 £/QALY) ist LAP + LET gegenüber einer Aromataseinhibitor-Monotherapie wahrscheinlich nicht kosteneffektiv, kann aber gegenüber TZ + ANA möglicherweise Kosteneffektivität erreichen, wobei der letztere Vergleich mit einer erheblichen Unsicherheit verbunden ist.